IGF1R and IR are structurally homologous heterotetrameric receptor tyrosine kinases sharing ~60% overall sequence identity (~84% in the kinase domain). IGF1R primarily mediates growth and survival signals through IGF-1/IGF-2 binding. IR primarily mediates metabolic (glucose uptake) signals through insulin binding. IR exists as two isoforms: IR-A (fetal, binds IGF-2 with high affinity) and IR-B (adult metabolic, insulin-selective). The two receptors can form IGF1R/IR hybrid heterodimers that preferentially bind IGF-1.

Several factors contributed: (1) Hyperglycemia from compensatory insulin resistance when IGF1R downregulation disrupted insulin/IGF signaling balance. (2) Lack of patient selection biomarkers — trials were not stratified by IGF1R expression or IGF pathway activation. (3) Feedback activation of alternative growth pathways (EGFR, HER2, IR) upon IGF1R blockade. Newer approaches address these issues through ADC strategies (cytotoxic payload delivery independent of signaling blockade), bispecific formats, and better patient stratification.

Use a binding panel with recombinant IGF1R ECD, IR-A ECD, and IR-B ECD proteins in matched formats (e.g., all His-tagged). Test candidate antibody binding by ELISA and SPR against all three targets. A selective anti-IGF1R antibody should show high affinity for IGF1R with no detectable binding to IR-A or IR-B. Additionally, test in a cell-based assay: stimulate IGF1R-expressing cells with IGF-1 ± candidate antibody and measure phospho-IGF1R inhibition without affecting insulin-stimulated phospho-IR in IR-expressing cells.

Six IGF binding proteins (IGFBP1-6) regulate IGF-1 and IGF-2 bioavailability by sequestering free IGFs in circulation and tissues. IGFBP3 is the most abundant and carries ~75% of circulating IGF-1 in a ternary complex with ALS (acid-labile subunit). When measuring serum IGF-1 by ELISA, sample pretreatment to dissociate IGF-1 from IGFBPs is critical for accurate free or total IGF-1 quantification — check whether your ELISA kit includes an extraction step.

IGF1R is overexpressed or hyperactivated in many solid tumors including breast cancer, NSCLC, colorectal cancer, prostate cancer, sarcomas (especially Ewing sarcoma), and hepatocellular carcinoma. Ewing sarcoma has the strongest preclinical rationale due to EWS-FLI1 fusion-driven IGF1R dependency. For patient selection, IHC staining with an anti-IGF1R antibody and/or phospho-IGF1R assessment can identify tumors with active IGF1R signaling.